1. Field of the Invention
The present invention relates to protein crosslinking reagents for the surgical repair of torn knee menisci in humans or similar connective tissue structures in animals such as the stifle joint meniscus in equines.
2. Related Art
The menisci of the knee are a pair of crescent-shaped fibrocartilaginous structures attached to the planar apical surface of the tibia. They contact the outer region of the femoral articular cartilage surface and as such play an important role in both load transmission and in maintaining the stability of the joint [1-6].
While 65-75% of the mass of the menisci consists of water, the remaining constituents are primarily proteins with the most common (75%) being type I collagen [7], and damage to this tissue is one of the most common causes of knee injury and results in surgery to some 850,000 patients per year in the US [8]. Symptoms of meniscal tears are primarily localized pain and swelling but, in cases where fragments of the damaged meniscus lodge between the articulating surfaces of the joint, catching sensations and (in the worst case) locking of the joint can occur.
The first line of treatment for meniscal tears are non-surgical, e.g. rest, icing, physical therapy and/or non-steroidal anti-inflammatory drug (NSAID) treatment. Surgery is indicated for patients who do not respond to physical therapy, who cannot or are unable to sacrifice the time required for potentially unsuccessful therapy and for those with locked joints.
Surgery is most commonly, but not exclusively, conducted arthroscopically to minimize further damage to the joint and to decrease patient recovery times. Damage to the outer periphery of either meniscus heals more readily than that to the inner portions [9,10], due to the lack of vasculature in the inner portion of the meniscus [11]. For this reason, tears of the inner meniscus are usually excised in a procedure known as a partial meniscectomy. In the remaining cases, tears are repaired using either suture or a variety of commercially available, fixing devices such as arrows, darts and tacks [12-14] in order to facilitate healing of the tear. These devices are generally constructed using biodegradable polymers such as polylactic or polyglycolic acid so that no subsequent surgery is required for their removal.
Although the latter class of devices provides temporary support to the tissue as it heals, they are in general not as strong as sutures [12,13]. However, because their use results in substantially reduced operating times and risk of complications to the patient, they are increasingly gaining favor [12,13].
While the above represents the most common approaches to the treatment of meniscal tears, other therapeutic modalities for meniscal repair can be used or are being explored experimentally. These include: stem cell therapy [15,16]; trephination from the vascular to avascular region to facility greater nutrient flow and promote in-growth of vasculature [17-19]; micro-fracture of the intercondylar notch which may release cytokines or autologous stem cells to aid in the repair process [20]; thermal welding of the tear [21]; enhancement of fibroblast proliferation using RF radiation [22,23]; use of fibrin clots to both provide stimuli for both chemotaxis and proliferation of regenerative cells [24-26], sometimes in conjunction with laser soldering [27]; meniscal or synovial rasping to promote healing via the release of growth factors from the tissue [28-31]; and synovial flap grafting at the repair site to provide vasculature [32].
In addition meniscal replacement using both artificial implants and allografts is becoming a treatment option in the case of severe tears where meniscectomy is the only other treatment option [33-40]. In this respect, the possibility of stabilizing allografts and artificial implants against biodegradation using ex vivo protein crosslinking has been explored [41-44]. The inventors are, however, unaware of any prior art with regard to crosslinking of the native meniscus in situ.